(2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid methyl ester, (CAS number 193153-04-7) has the International Nonproprietary Name Otamixaban and shows the structure illustrated in Formula I:

(2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[4-(1-oxy-pyridin-4-yl) benzoylamino]-butyric acid methyl ester (Otamixaban, Formula I) use in the preparation of a medicament for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa has been disclosed in WO97/24118.
Factor Xa is the penultimate enzyme in the coagulation cascade. Factor Xa (fXa) is a critical serine protease situated at the confluence of the intrinsic and extrinsic pathways of the blood coagulation cascade. FXa catalyses the conversion of prothrombin to thrombin via the prothrombinase complex. Its singular role in thrombin generation, coupled with its potentiating effects on clot formation render it an attractive target for therapeutic intervention.
Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by Otamixaban. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition is achieved by administering the compound either by continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin. In vivo experiments have demonstrated that Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis. In addition, recent clinical findings indicate that Otamixaban is efficacious, safe and well tolerated in humans and therefore has considerable potential for the treatment of acute coronary syndrome (K. R. Guertin and Yong-Mi Choi; 2007; Current Medicinal Chemistry, Vol. 14, No. 23; p. 2471-2481). Clinical findings in a dose-ranging clinical trial indicate that Otamixaban reduced prothrombin fragments 1+2 significantly more than unfractionated heparin at the highest dose regimen (Cohen et al., Circulation, Vol. 115, No. 20, May 2007, pages 2642-2651), but said clinical findings do not show data in comparison of age or renal impairment. Further clinical trials demonstrated that Otamixaban induces dose-dependent, rapid direct factor Xa inhibition in patients with stable coronary artery disease who are taking their usual comedication, some of whom have mild renal impairment (Hinder et al., Clinical Pharmacology and Therapeutics, Vol. 80, No. 6, 2006, pages 691-702).
Acute coronary syndromes (ACS) are characterised by an imbalance between myocardial oxygen supply and demand. The most common cause is the reduced myocardial perfusion that results from coronary artery narrowing caused by a thrombus that has developed on a disrupted atherosclerotic plaque. Within the diagnosis of ACS two major subtypes can be distinguished that are non-ST elevation acute coronary syndrome (NSTE-ACS) and ST-elevation myocardial infarction (STE-MI). NSTE-ACS corresponds to a partial thrombotic occlusion of a coronary vessel with more or less pronounced ischemia. The main aim of treatment for these conditions is to prevent a sudden total occlusion of the arteries. STE-MI is characterised by a sudden total thrombotic occlusion of a coronary vessel resulting in ischemia of the heart. It needs to be treated urgently, within the initial 6-12 hours, and preferably 2 hours following the diagnosis. The goal is to restore patency (blood flow) of the occluded vessel. This can be performed by angioplasty, percutaneous coronary intervention or coronary artery bypass grafting (CABG). CABG is an open heart surgery in which a prosthesis or a section of a vein is grafted from the aorta onto one of the coronary arteries, bypassing a narrowing or blockage in the coronary artery. The operation is performed in coronary artery disease to improve the blood supply to the heart muscle and to relieve anginal pain. Coronary arteriography pinpoints the areas of obstruction before surgery. Under general anesthesia and with the use of a cardiopulmonary bypass machine, one end of a 15- to 20-cm prosthesis or a segment of saphenous vein from the patient's leg is grafted to the ascending aorta. The other end is sutured to the clogged coronary artery at a point distal to the stoppage. The internal mammary artery may also be used as graft tissue. Usually double or triple grafts are done for multiple areas of blockage. After surgery, close observation in an intensive care unit is essential to ensure adequate ventilation and cardiac output.
Risk scores have been developed that regroup markers of the acute thrombotic process and other markers to identify patients with high-risk for total occlusion of vessels; in the following high-risk patients for coronary artery disease or peripheral arterial disease. In addition to the estimation of the risk, the assessment of the cardiac biomarker of necrosis, especially the cardiac troponins, are performed in order to select the treatment strategy of choice. It has been demonstrated during the last years that patients with moderate-to-high risk patients benefit from an early invasive strategy, where patients are brought early to a catheter lab (by the next day, or two) for angiography followed by a percutaneous coronary intervention (PCI) or a CABG. In recent US treatment guidelines for high-risk patients an invasive strategy is recommended for moderate-to-high risk patients while for lower risk patients a conservative strategy is preferred. However, timely access to invasive treatment is often more important for the decision than risk assessment.
In all high-risk patients (with invasive or conservative strategy) a standard medical therapy is indicated including aspirin, clopidogrel and anticoagulant therapy.
The primary discussions in medical literature today is focused on the moderate-to-high-risk patients, who are scheduled to undergo an early (≦48-72 h) diagnostic catheterization and coronary intervention. Aspirin, clopidogrel, GP IIb/IIIa inhibitors (including eptifibatide and abciximab), unfractionated heparin, bivalirudin, enoxaparin, fondaparinux are all recommended in the most recent guidelines indicating their recognition as standard of care for patients with moderate-to-high-risk.
Use of such a multi-tiered combination pharmacologic approach, however, has not been formally investigated and may result in increased risk of bleeding complications, greater complexity of treatment and increased costs. Further the presently used combination therapy of heparin and GP IIb/IIIa inhibitor is efficacious but causes bleeding in high-risk patients receiving dual oral antiplatelet therapy with aspirin and clopidogrel. Thus, the optimal anti-thrombotic regimen for moderate-to-high-risk patients remains to be found.
It is an object of the present invention to find a medical treatment, which does not have the disadvantages mentioned and provides a reduction of bleeding rates in high-risk patients suffering from non-ST elevation acute coronary syndrome and planned to undergo coronary artery bypass grafting.
It has now unexpectedly been found that Otamixaban offers improved management of high-risk patients suffering from non-ST elevation acute coronary syndrome. If said patients are already being treated by administration of Otamixaban and are planned to undergo coronary artery bypass grafting (CABG), administration of Otamixaban to said patients will be discontinued at least 3 hours particularly 3 to 6 hours more particularly 6 hours or more prior to said coronary artery bypass grafting (CABG). Unexpectedly, said high-risk patents show a reduced risk of bleeding.